CN108042485B - A kind of Altrenogest preparation and preparation method thereof - Google Patents
A kind of Altrenogest preparation and preparation method thereof Download PDFInfo
- Publication number
- CN108042485B CN108042485B CN201711087540.8A CN201711087540A CN108042485B CN 108042485 B CN108042485 B CN 108042485B CN 201711087540 A CN201711087540 A CN 201711087540A CN 108042485 B CN108042485 B CN 108042485B
- Authority
- CN
- China
- Prior art keywords
- altrenogest
- preparation
- finish
- medical fluid
- porous chitosan
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of Altrenogest preparations and preparation method thereof, belong to veterinary drug technical field.Altrenogest preparation of the invention is by including that the raw material of following mass percent is made, 0.3~0.5% Altrenogest, 0.9~1.1% benzyl alcohol, 0.012~0.016% antioxidant, 3.0~6.5% modified porous chitosan microballs, surplus are finish, and antioxidant is tertiary butyl-4-hydroxy anisole (BHA) and 2, the mixture of 6- di-tert-butyl p-cresol (BHT), finish are that peanut oil, soybean oil, castor oil or palm oil are any one or more of；Preparation method is, antioxidant and benzyl alcohol are added in finish, it stirs evenly, Altrenogest and modified porous chitosan microball is added, stirs evenly, obtain primary medical fluid, primary medical fluid is added in remaining finish, is stirred evenly, secondary medical fluid is obtained, secondary medical fluid obtains Altrenogest preparation through membrane filtration.Altrenogest better stability of preparation of the invention, bioavilability are high.
Description
Technical field
The invention belongs to veterinary drug technical field, it is related to a kind of Altrenogest preparation and preparation method thereof.
Background technique
Altrenogest is a kind of 21 carbon steroid progestational hormone of triolefin of synthesis, belongs to 19- demethyl-stosterone, is a kind of
Oral active progestational hormone.As all steroids, Altrenogest fat-soluble can be infiltrated through in target cell so by itself
It plays a role in conjunction with special receptor afterwards, inhibits the release of promoting sexual gland hormone to be similar to the binding mode of Natural progesterone.
Altrenogest by inhibiting endogenous promoting sexual gland hormone LH and FSH concentration in blood, the ovarian follicle that makes to increase (>20~25 millis
Rice) it shrinks back, and then block heat and ovulation.Followed by it will appear after all increase ovarian follicles are shunk back in the rear half stage of medication
The peak of one FSH secretion, this will starting new round ovarian follicular growth and maturation.Phase meeting follower LH secretion has rule after the treatment
The increase of rule promotes the growth and maturation of ovarian follicle.This endocrine effect can be such that treated young dam enters after drug withdrawal
Heat, therefore Altrenogest can be used for domestic animal synchronization of Estrus.Estrus synchronization can be such that domestic animal delivery time concentrates, convenient for concentrating
Feeding concentrates wean, all-in and all-out, the same period to enter next breeding cycle, effectively improves the breeding potential of domestic animal, reduces cause of disease
Propagation, carry out stringent epidemic prevention system and guarantee Biosecurity system, be conducive to scale management.
It there is no Altrenogest preparation in China's veterinary markets at present, European EMA and U.S. FDA approved Altrenogest
Synchronization of estrus for induction of mare and sow.But Altrenogest acid condition and illumination and thermal environment stability inferior compared with
Difference will receive certain destruction, in turn results in its bioavilability is low, dosage increases, improves drug cost etc., limits significantly
Its application in veterinary clinic.
Chitosan is to slough a kind of Natural polycations polysaccharide prepared by part or all of acetyl group by chitin to spread out
Biology.Chitosan has the good characteristics such as nontoxic, biodegradable, is widely used in biotechnology, food, drug, makeup
The fields such as product and medicine.But the activity of chitosan is influenced by factors such as deacetylation itself and molecular weight, most
Dissolubility is poor in number solvent.
Summary of the invention
The purpose of the present invention is in view of the above-mentioned problems existing in the prior art, proposing, a kind of stability is good, biological utilisation
Spend high Altrenogest preparation and preparation method thereof.
Object of the invention can be realized by the following technical scheme：
A kind of Altrenogest preparation, the Altrenogest preparation are made of the raw material including following mass percent,
Altrenogest：0.3~0.5%,
Benzyl alcohol：0.9~1.1%,
Antioxidant：0.012~0.016%,
Modified porous chitosan microball：3.0~6.5%
Finish：Surplus,
The antioxidant is the mixing of tertiary butyl-4-hydroxy anisole (BHA) and DBPC 2,6 ditertiary butyl p cresol (BHT)
Object, the finish are that peanut oil, soybean oil, castor oil or palm oil are any one or more of.
The present invention joined modified porous chitosan microball, porous structure and chitosan itself in Altrenogest preparation
Property determine that Altrenogest with biggish specific surface area and stronger adsorption capacity, can be adsorbed on the table of its hole by it
Face plays a protective role to Altrenogest under gastric acid and photo-thermal environment as the absorption carrier of Altrenogest, and it is pregnant to improve allyl
The stability and bioavilability of plain preparation reduce dosage.Bearer of the modified porous chitosan microball as Altrenogest,
Changing Altrenogest makes it more preferably into intracorporal mode and distribution in vivo, the rate of release that can control Altrenogest
Ground plays effect.Moreover, chitosan surface have a large amount of basic group hydroxyl and amino, in gastric acid environment can first with stomach
Acid effect, can further avoid destruction of the gastric acid to Altrenogest.Meanwhile chitosan also has bacteriostatic activity, and does not influence to have
The growth of beneficial bacteria can act synergistically with benzyl alcohol, play bacteriostasis in Altrenogest preparation.Modified porous chitosan microball
Content is very few, does not have above-mentioned effect, and content excessively will affect the release and absorption of Altrenogest in vivo.Chitosan also has
Good bioactivity and biodegradability, nontoxic and biocompatibility is good, and when use will not damage domestic animal.This
Invention effectively increases its dissolubility in finish by being modified to Porous Chitosan Microspheres, so that porous chitosan is micro-
Ball can give full play to its effect.
Benzyl alcohol has preferable fungistatic effect, and can promote dissolution of the Altrenogest in finish and more in modification
Absorption on the chitosan microball of hole makes each component in raw material reach best Fusion Strain, to make the drug effect of Altrenogest preparation
Reach optimum state.BHA and BHT has synergistic effect, plays antioxidation, effectively extends effectively making for Altrenogest preparation
Use the phase.
Preferably, the Altrenogest preparation is made of the raw material of following mass percent,
Altrenogest：0.4%,
Benzyl alcohol：1.04%,
BHA：0.007%,
BHT：0.007%,
Modified porous chitosan microball：5.3%,
Finish：Surplus.
Preferably, the surface of the modified porous chitosan microball is connected with aliphatic chain by graft reaction.
The present invention is by connecting aliphatic chain, aliphatic chain and finish compatibility in Porous Chitosan Microspheres surface graft modification
Height, and isolation can be formed between chitosan microball, the active group on aliphatic chain can generate connection with Altrenogest
Effect, to increase solubility and dispersibility of the Porous Chitosan Microspheres in finish, and the adsorption energy to Altrenogest
Power.
Preferably, the carbon number of the aliphatic chain is between 3~10.
Within the above range by the carbon number control of aliphatic chain, reason is that aliphatic chain is too long and is easy in chitosan the present invention
Microsphere surface causes steric hindrance to act on, and influences the suction-operated to Altrenogest.
Preferably, the partial size of the modified porous chitosan microball is 1~4 μm.
Modified porous chitosan microball partial size is too small, is unfavorable for the absorption of Altrenogest, and is unfavorable for point in finish
It dissipates, partial size is excessive, is unfavorable for release of the Altrenogest in organism and is absorbed and utilized.
Preferably, the porosity of the modified porous chitosan microball is 52~70%, pore size is 28~53nm.
Suitable porosity and pore size are conducive to the absorption and release of Altrenogest, and aperture is excessive, is unfavorable for allyl
Stability of the pregnant element in gastric acid environment.
Preferably, the finish is soybean oil.
Another object of the present invention is to provide a kind of preparation method of Altrenogest preparation, the preparation method includes such as
Lower step：
S1, after taking the 25~30% of finish total weight to be cooled to 50~70 DEG C, antioxidant and benzyl alcohol is added, stirring is equal
It is even, obtain oil solution；
S2, after oil solution is cooled to 40 DEG C or less, Altrenogest and modified porous chitosan microball is added, stirring is equal
It is even, obtain primary medical fluid；
S3, primary medical fluid is added in remaining finish, is stirred evenly, obtain secondary medical fluid；
S4, by secondary medical fluid respectively through 50.0 μm, 30.0 μm of filter membrane secondary filtrations, obtain Altrenogest preparation.
It is kept in whole preparation process of the present invention under the conditions of lower temperature, can effectively prevent hot conditions to raw material
The destruction of each component, and reduce energy consumption and production cost and the requirement to process equipment；Especially in step S2
It is middle that whipping temp is reduced to 40 DEG C hereinafter, the destruction in hot conditions to Altrenogest can be effectively prevent, improve allyl
The drug effect of pregnant element preparation.
Preferably, in the step S1, temperature when stirring is 50~70 DEG C, and mixing speed is 80~120rpm, is stirred
Mixing the time is 5~10min.
Preferably, in the step S2, temperature when stirring is 30~40 DEG C, and mixing speed is 80~120rpm, is stirred
Mixing the time is 20~30min.
Preferably, in the step S3, temperature when stirring is 20~30 DEG C, and mixing speed is 150~200rpm, is stirred
Mixing the time is 20~30min.
Compared with prior art, the invention has the advantages that：
(1) Altrenogest preparation of the invention can effectively adjust livestock endocrine, carry out progestogenic of promoting the sexual maturity, and control livestock is regular
Heat is produced with realizing that livestock grouping is pre-, achievees the purpose that all-in and all-out, so that the production efficiency and industry of livestock be greatly improved
Change management level；
(2) Altrenogest preparation of the invention is able to maintain the stability under gastric acid and light and heat condition, can effectively improve
Availability of the storage life and Altrenogest of Altrenogest preparation in organism；
(3) Altrenogest preparation of the invention has certain slow releasing function, administration number of times can be reduced, to improve labour
Efficiency reduces artificial and management cost.
Specific embodiment
The following is specific embodiments of the present invention, and technical scheme of the present invention will be further described, but the present invention is simultaneously
It is not limited to these embodiments.
The Altrenogest preparation and preparation method thereof in the present invention is further explained below by specific embodiment.
Examples 1 to 4
Altrenogest preparation in Examples 1 to 4 is made of the raw material including following mass percent,
Altrenogest：0.3~0.5%,
Benzyl alcohol：0.9~1.1%,
Antioxidant：0.012~016%,
Modified porous chitosan microball：3.0~6.5%
Finish：Surplus,
Antioxidant is the mixture of tertiary butyl-4-hydroxy anisole (BHA) and 2,6-di-tert-butyl p-cresol (BHT), oil
Agent is that peanut oil, soybean oil, palm oil or Miglyol 812 are any one or more of.
The surface of modified porous chitosan microball is connected with aliphatic chain by graft reaction, and the carbon number of aliphatic chain is 3~10
Between.The partial size of modified porous chitosan microball is 1~4 μm, and porosity is 52~70%, and pore size is 28~53nm.
Each raw material and its mass percent are as shown in table 1 in Examples 1 to 4, the structure ginseng of modified porous chitosan microball
Number is as shown in table 2.
Table 1：Each raw material and its mass percent in Examples 1 to 4
Table 2：The structural parameters of modified porous chitosan microball
Embodiment 5
(1), by the raw material components and mass percent preparation raw material in embodiment 2, solid material is crossed into 60 mesh standby
With；
(2), after taking the 25% of finish total weight to be cooled to 50 DEG C, antioxidant and benzyl alcohol is added, 50 DEG C of temperature,
5min is stirred under 120rpm revolving speed, obtains oil solution；
(3), oil solution is cooled to 30 DEG C, Altrenogest and modified porous chitosan microball is added, 30 DEG C of temperature,
30min is stirred under 120rpm revolving speed, obtains primary medical fluid；
(4), primary medical fluid is added in remaining finish, stirs 30min under 25 DEG C of temperature, 150rpm revolving speed, obtains
To secondary medical fluid；
(5), secondary medical fluid is obtained into Altrenogest preparation respectively through 50.0 μm, 30.0 μm of filter membrane secondary filtrations.
Embodiment 6
(1), by the raw material components and mass percent preparation raw material in embodiment 2, solid material is crossed into 60 mesh standby
With；
(2), after taking the 30% of finish total weight to be cooled to 60 DEG C, antioxidant and benzyl alcohol is added, 60 DEG C of temperature,
10min is stirred under 100rpm revolving speed, obtains oil solution；
(3), oil solution is cooled to 35 DEG C, Altrenogest and modified porous chitosan microball is added, 35 DEG C of temperature,
25min is stirred under 100rpm revolving speed, obtains primary medical fluid；
(4), primary medical fluid is added in remaining finish, stirs 25min under 30 DEG C of temperature, 180rpm revolving speed, obtains
To secondary medical fluid；
(5), secondary medical fluid is obtained into Altrenogest preparation respectively through 50.0 μm, 30.0 μm of filter membrane secondary filtrations.
Embodiment 7
(1), by the raw material components and mass percent preparation raw material in embodiment 2, solid material is crossed into 60 mesh standby
With；
(2), after taking the 27% of finish total weight to be cooled to 70 DEG C, antioxidant and benzyl alcohol is added, 70 DEG C of temperature,
8min is stirred under 80rpm revolving speed, obtains oil solution；
(3), oil solution is cooled to 40 DEG C, Altrenogest and modified porous chitosan microball is added, 40 DEG C of temperature,
20min is stirred under 80rpm revolving speed, obtains primary medical fluid；
(4), primary medical fluid is added in remaining finish, stirs 22min under 20 DEG C of temperature, 200rpm revolving speed, obtains
To secondary medical fluid；
(5), secondary medical fluid is obtained into Altrenogest preparation respectively through 50.0 μm, 30.0 μm of filter membrane secondary filtrations.
Embodiment 8
(1), by the raw material components and mass percent preparation raw material in embodiment 2, solid material is crossed into 60 mesh standby
With；
(2), after taking the 26% of finish total weight to be cooled to 65 DEG C, antioxidant and benzyl alcohol is added, 65 DEG C of temperature,
7min is stirred under 115rpm revolving speed, obtains oil solution；
(3), oil solution is cooled to 35 DEG C, Altrenogest and modified porous chitosan microball is added, 35 DEG C of temperature,
25min is stirred under 110rpm revolving speed, obtains primary medical fluid；
(4), primary medical fluid is added in remaining finish, stirs 20min under 28 DEG C of temperature, 180rpm revolving speed, obtains
To secondary medical fluid；
(5), secondary medical fluid is obtained into Altrenogest preparation respectively through 50.0 μm, 30.0 μm of filter membrane secondary filtrations.
Embodiment 9~11
Respectively by the raw material components and mass percent preparation raw material in embodiment 1,3,4, according to the preparation side of embodiment 6
The preparation of method progress Altrenogest preparation.
Comparative example 1
Modified porous chitosan microball is not added in the preparation process of Altrenogest preparation, it is other same as Example 6.
Comparative example 2
The Altrenogest preparation of commercially available other manufacturers.
Stability experiment is carried out using Altrenogest preparation obtained in embodiment, comparative example 1 and comparative example 2 and animal is real
It tests, experimental method and result are as follows：
(1) stability experiment
Experimental method：By the Altrenogest preparation in embodiment 6, comparative example 1 and comparative example 2 respectively at high temperature (60 DEG C) and
Under the conditions of intense light irradiation degree (4500lx ± 500lx), influence factor experiment investigation is carried out, was sampled respectively at the 5th day and the 10th day, is surveyed
Determine content and related substance, the results are shown in Table 3：
3 Altrenogest influence factor test result of table
The experimental result of table 3 shows that the Altrenogest preparation stability ratio for being added to modified porous chitosan microball does not add
Modified porous chitosan microball and other commercial product will be got well.Using the allyl prepared in embodiment 5,6~11 in the present invention
Pregnant element preparation carries out above-mentioned experiment, and the result of embodiment 6 is close in obtained result and table 3.
(2) pharmacokinetic studies
Experimental animal：8~September age replacement gilt 16 passes through 1~2 oestrous cycle, 95~105kg of weight range,
Test method：Replacement gilt is divided into two groups, every group 8, feeds embodiment 6, the Altrenogest in comparative example 1 respectively
Preparation.
After fasting 12h, material spray administration is carried out by the dosage of 20mg/ days/head (being equivalent to 0.2mg/kg B.W.), is continuously given
Medicine 18 days.Specifically first a feed is divided into two parts when administration, is administered to a copy of it material spray, is supervised after pig eats completely completely again
To an other foddering, guarantee that every pig every time all eats up feed, after administration in first day and the 18th day, respectively after administration
20min, 40min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, blood sample is acquired for 24 hours, other blood sampling points are every
(8 a.m.) and 2 pm before day administration after successive administration 18 days, acquired blood sample in the 20th day 2 pm.
Parameters in blood sample after material spray administration for the first time：Terminal eliminates half-life period (t1/2), peak time (Tmax), blood medicine peak
It is worth concentration (Cmax), area under the drug-time curve (AUC0-t) and mean residence time (MRT) is as shown in table 4, continuous material spray on the 18th is given
Each parameter in blood sample after medicine：Mean steady state concentration of blood drug (Css), degree of fluctuation, AUC0-tWith mean residence time (MRT) such as table 5
It is shown.
Table 4：Parameters in blood sample after material spray administration for the first time
Table 5：Each parameter in blood sample after the continuous administration of material spray on the 18th
By table 4 and table 5 it is found that compared with comparative example 1, Altrenogest obtained is in single-dose in the embodiment of the present invention 6
Peak time (T afterwardsmax) close, and terminal eliminates half-life period (t1/2), mean residence time (MRT) and continuous material spray on the 18th give
Mean residence time (MRT) is relatively long after medicine, illustrates Altrenogest preparation of the invention long action time in vivo, tool
There are certain slow release effect, while area under the drug-time curve (AUC0-t) higher, illustrate bioavilability height.
(3) induction sow estrus synchronization test
Experimental animal：215 age in days replacement gilts, original body mass, heredity are similar, and through veterinary inspection, behaviouristics, physiology
With the normal healthy replacement gilt 120 of appetite.All experimental animals are fed according to the requirement in growth period with standard mixed fodder,
Nutritional ingredient must not arbitrarily be increased or decreased, carry out feeding management according to a conventional method, carried out before testing necessary immunization inocultation and
Expelling parasite executes stringent Antiepidemic sterilizing measure during test.
Test method：
Sow is randomly divided into 5 groups, respectively tests I group, II group of test, test III group, 1 group of comparative example, 2 groups of comparative example
Drug control group and negative control group, every group 20, test I group, test II group, test III group respectively according to 10mg, 20mg,
Altrenogest preparation obtained in the dosage feeding embodiment 6 of 40mg, 1 group of the comparative example dosage according to 20mg feed comparative example 1
In Altrenogest preparation obtained, 2 groups of drug control groups of comparative example feed the allyl of other manufacturers according to the dosage of 20mg
Pregnant element preparation, negative control group feed 5ml soybean oil, continuous feeding 18 days.
It lures feelings method to detect oestrus of sow by boar, record heat situation and breeds to heat sow, breeding
Later 23 days, 28 days B ultrasound identification Pregnancies.
Table 6：Replacement gilt heat is influenced after Altrenogest feeding
As shown in Table 6, Altrenogest preparation of the invention has the effect of significantly adjusting sow estrus synchronization, test group
Difference is not significant (P > 0.05) between 2 groups of drug control groups of comparative example, during test, test group and comparative example group and yin
Property control group compare, rutting rate difference is not significant (P > 0.05).Compared with 1 group of comparative example, Altrenogest system of the invention
Agent is more preferable in the effect of control oestrus of sow.
Analysis sow most concentrates sow in adjacent two days, 9 days that rutting rate and Altrenogest is concentrated to stop heat after feeding 9 days
Breeding ratio counts the concentration degree of replacement gilt heat, the results are shown in Table 7.
Table 7：Altrenogest stops different time oestrus of sow and breeding situation statistics after feeding
By table 6 and table 7 it is found that Altrenogest preparation of the invention has the effect of significantly promoting to concentrate heat, closing
Under suitable adding proportion, oestrus of sow can be controlled in 2~3 days, test group, comparative example group replacement gilt most concentrate adjacent two
Difference is extremely significant (P < 0.01) compared with negative control group for its heat ratio；Test group sow most concentrates rutting rate in 9 days
Difference is not significant between comparative example group, but test group, comparative example group significant difference (P < 0.05) compared with negative control group；
Stop feeding in 9 days, test group, the rutting rate of comparative example group are distinguished compared with negative control group, extremely significant (the P < of difference
0.01).The result shows that Altrenogest preparation can make sow synchronization of estrus, and heat is more concentrated in adjacent 2~3 days.From dosage
Upper analysis, the effect that the additive capacity of 10mg, 20mg, 40mg have preferable promotion synchronization of estrus, synchronize gestation, but 10mg's
Dosage easily causes oral dose insufficient in production application, influences using effect, the dosage higher operating costs of 40mg, therefore
The dosage of 20mg is more appropriate.
(4) oral acute toxicity testing
Experiment one
Experimental animal：Cleaning grade health ICR mouse 40,20 ± 2g of weight, half male and half female is provided by Yangzhou University.
Test method：Mouse is divided into first group (20, half male and half female) and second group (20, half male and half female), first
Group is divided into five groups (every group 4, half male and half female) again, respectively according to 100,500,1000,2500,5000mg/kg after fasting 12h
B.w. the Altrenogest preparation in (the pure content of Altrenogest in Altrenogest preparation) five poisoning dosage feeding embodiments 6,
Do not cause death；Second group of mouse is fed with the poisoning dosage of 5000mg/kg b.w. again, is observed continuously after feeding
14 days.
Experiment two
Experimental animal：Cleaning grade health ICR rat 40,200 ± 20g of weight, half male and half female is provided by Yangzhou University.
Test method：It carries out, is observed continuously after feeding 14 days according to the method for oral acute toxicity testing one.
Oral acute toxicity testing one and oral acute toxicity testing two are during observation, and mouse and rat clinical manifestation are just
Often, without obvious nervous symptoms, skin and coat are without exception, until the observation period terminates, do not find poisoning and the phenomena of mortality；Experiment knot
Dissect survival mice after beam, internal organs and reproductive organs including Stomach duodenum do not find that obvious eye sees disease
Become.The result shows that Altrenogest preparation of the invention is greater than 5000mg/kg b.w. to the LD50 of passing through mouth of mouse, acute toxicity compared with
It is low.
In conclusion Altrenogest preparation in the present invention has and apparent promotes domestic animal estrus synchronization, same period gestation
Effect will not cause stress reaction to dam, and the modified porous chitosan microball added in formulation process is to Altrenogest
It plays a protective role, the unstability of Altrenogest under gastric acid and light and heat condition can be reduced, improve its utilization in vivo
Degree, and there is certain slow release effect, administration number of times and dosage can be reduced.
Specific embodiment described herein is only an example for the spirit of the invention.The neck of technology belonging to the present invention
The technical staff in domain can make various modifications or additions to the described embodiments or replace by a similar method
In generation, however, it does not deviate from the spirit of the invention or beyond the scope of the appended claims.
Claims (6)
1. a kind of Altrenogest preparation, which is characterized in that the Altrenogest preparation is made of the raw material of following mass percent,
Altrenogest：0.3 ~ 0.5%,
Benzyl alcohol：0.9 ~ 1.1%,
Antioxidant：0.012 ~ 0.016%,
Modified porous chitosan microball：3.0 ~ 6.5%,
Finish：Surplus,
The antioxidant is tertiary butyl-4-hydroxy anisole（BHA）With 2,6- di-tert-butyl p-cresol（BHT）Mixture, institute
Stating finish is that peanut oil, soybean oil, castor oil or palm oil are any one or more of,
The partial size of the modified porous chitosan microball is 1 ~ 4 μm, and porosity is 52 ~ 70%, and pore size is 28 ~ 53nm, described
Modified porous chitosan microball is the Porous Chitosan Microspheres that surface is connected with aliphatic chain by graft reaction, the aliphatic chain
Carbon number is between 3 ~ 10；
The Altrenogest preparation is made of the preparation method including the following steps：
S1, after taking the 25 ~ 30% of finish total weight to be cooled to 50 ~ 70 DEG C, antioxidant and benzyl alcohol is added, stirs evenly, obtains oil
Solution；
S2, after oil solution is cooled to 40 DEG C or less, Altrenogest and modified porous chitosan microball is added, stirs evenly, obtains
To primary medical fluid；
S3, primary medical fluid is added in remaining finish, is stirred evenly, obtain secondary medical fluid；
S4, by secondary medical fluid respectively through 50.0 μm, 30.0 μm of filter membrane secondary filtrations, obtain Altrenogest preparation.
2. Altrenogest preparation according to claim 1, which is characterized in that the Altrenogest preparation is by following quality hundred
The raw material of ratio is divided to be made,
Altrenogest：0.4%,
Benzyl alcohol：1.04%,
BHA：0.007%,
BHT：0.007%,
Modified porous chitosan microball：5.3%,
Finish：Surplus.
3. Altrenogest preparation according to claim 1, which is characterized in that the finish is soybean oil.
4. Altrenogest preparation according to claim 1, which is characterized in that in the step S1, temperature when stirring is equal
It is 50 ~ 70 DEG C, mixing speed is 80 ~ 120rpm, and mixing time is 5 ~ 10min.
5. Altrenogest preparation according to claim 1, which is characterized in that in the step S2, temperature when stirring is
30 ~ 40 DEG C, mixing speed is 80 ~ 120rpm, and mixing time is 20 ~ 30min.
6. Altrenogest preparation according to claim 1, which is characterized in that in the step S3, temperature when stirring is
20 ~ 30 DEG C, mixing speed is 150 ~ 200rpm, and mixing time is 20 ~ 30min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711087540.8A CN108042485B (en) | 2017-11-08 | 2017-11-08 | A kind of Altrenogest preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711087540.8A CN108042485B (en) | 2017-11-08 | 2017-11-08 | A kind of Altrenogest preparation and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108042485A CN108042485A (en) | 2018-05-18 |
| CN108042485B true CN108042485B (en) | 2018-11-27 |
Family
ID=62118969
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711087540.8A Active CN108042485B (en) | 2017-11-08 | 2017-11-08 | A kind of Altrenogest preparation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108042485B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109260208B (en) * | 2018-08-30 | 2021-04-30 | 宁波三生生物科技有限公司 | Veterinary altrenogest preparation and preparation method thereof |
| CN109464400A (en) * | 2018-12-29 | 2019-03-15 | 佛山市南海东方澳龙制药有限公司 | Altrenogest solid pharmaceutical preparation and its preparation method and application |
| CN112137975A (en) * | 2020-10-30 | 2020-12-29 | 厦门汇承药业有限公司 | Altrenogest tablet and dry preparation method thereof |
| CN114344242A (en) * | 2022-01-04 | 2022-04-15 | 北京菲繁生物技术有限公司 | Alsopreglin soft sweets and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804712A (en) * | 2014-01-23 | 2014-05-21 | 北京化工大学常州先进材料研究院 | Preparation of porous and aperture-controllable chitosan microspheres |
| WO2016054741A1 (en) * | 2014-10-08 | 2016-04-14 | Arivac Inc. | Altrenogest formulation and uses thereof for estrus synchronisation in animals |
| CN105816466A (en) * | 2016-03-17 | 2016-08-03 | 刘文善 | Veterinary synchronized estrus promoter and preparation method thereof |
| CN105919932A (en) * | 2016-06-13 | 2016-09-07 | 上海同仁药业股份有限公司 | Altrenogest oral liquid and preparation method thereof |
-
2017
- 2017-11-08 CN CN201711087540.8A patent/CN108042485B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804712A (en) * | 2014-01-23 | 2014-05-21 | 北京化工大学常州先进材料研究院 | Preparation of porous and aperture-controllable chitosan microspheres |
| WO2016054741A1 (en) * | 2014-10-08 | 2016-04-14 | Arivac Inc. | Altrenogest formulation and uses thereof for estrus synchronisation in animals |
| CN105816466A (en) * | 2016-03-17 | 2016-08-03 | 刘文善 | Veterinary synchronized estrus promoter and preparation method thereof |
| CN105919932A (en) * | 2016-06-13 | 2016-09-07 | 上海同仁药业股份有限公司 | Altrenogest oral liquid and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 带孔壳聚糖微球的制备及其释药性研究;柴瑞霞等;《山东化工》;20151231;第44卷;11-13 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108042485A (en) | 2018-05-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108042485B (en) | A kind of Altrenogest preparation and preparation method thereof | |
| Yaakub et al. | Effect of type and quantity of concentrates on superovulation and embryo yield in beef heifers | |
| De Leeuw et al. | Pimozide-LHRHa-induced breeding of the African catfish, Clarias gariepinus (Burchell) | |
| KR100886795B1 (en) | Animal food and method | |
| CN101869222B (en) | Feed additive for improving reproductive capacity of boar and preparation method thereof | |
| CN101869221B (en) | Feed additive for improving reproductive capacity of sow and preparation method thereof | |
| CN103179963B (en) | Compositions for the abscisic acid of animal health | |
| CN1050732C (en) | Method for breeding infant livestock and feed composition | |
| CN109260208A (en) | A kind of Altrenogest preparation for animals and preparation method thereof | |
| CN101589772B (en) | Chinese herbal medicine feed additive for fattening cattle and application thereof | |
| CA2963871A1 (en) | Altrenogest formulation and uses thereof for estrus synchronisation in animals | |
| Nigussie | A review on the role of energy balance on reproduction of dairy cow | |
| CN102524584B (en) | Composite pig feed additive for effectively preventing edema of pigs | |
| CN102696901B (en) | Feed for meat-producing chick | |
| Xu et al. | Polyunsaturated fatty acid supplements could considerably promote the breeding performance of carp | |
| CN103493983B (en) | Feed additive for improving fur quality of fur-bearing animal and manufacturing method thereof | |
| CN104997794B (en) | A kind of long-acting multi-vitamins oral latex emulsion for animals and preparation method thereof | |
| CN101869225B (en) | Feed additive for improving pregnancy rate of sows and preparation method thereof | |
| CN106260623A (en) | A kind of farmers' self-control sheep raising feedstuff and preparation method | |
| CN104664168B (en) | A kind of piglet specific complex vitamin microemulsion preparation and its preparation method and application | |
| Wang et al. | Effects of dietary energy density in the dry period on the production performance and metabolism of dairy cows | |
| JP2022056858A (en) | Ergothioneine-containing food or feed | |
| EP3554262A1 (en) | Using of lycium barbarum based formulations to improve female fertility | |
| CN109480108A (en) | A kind of composition and preparation method thereof shortening oestrus of sow interval | |
| US20040137131A1 (en) | Maca products and their uses |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 159 Buzheng East Road, Wangchun Industrial Park, Haishu District, Ningbo City, Zhejiang Province, 315000 Patentee after: Ningbo Sansheng Biotechnology Co.,Ltd. Address before: 159 Buzheng East Road, Wangchun Industrial Park, Haishu District, Ningbo City, Zhejiang Province, 315000 Patentee before: NINGBO SANSHENG BIOLOGICAL TECHNOLOGY Co.,Ltd. |